The presence of enzymes, e.g., carbonic anhydrase (ca) and 5'-nucleotidase, in the myelin sheath has been substantiated by quantitative biochemical data and immunocytochemical localization. Most recently, investigations into the functions of these enzymes in myelin and glial cells were undertaken. In particular, the high specific activities of both acetyl-CoA carboxylase and ca in oligodendrocytes suggested a role for ca in the biosynthesis of myelin lipids. The availability of a carbonic-anhydrase-- deficient mutant mouse will now provide a unique opportunity to test more directly certain hypothetical functions of ca: e.g., the putative roles in the synthesis of myelin lipids and in compaction of the myelin sheath. Parameters that will be compared in the brains of mutant and control mice include myelin yields, ultrastructure of the myelin sheath and susceptibility to pentylenetetrazole seizures. A second series of experiments will be concerned with two isoenzymes of glutathione-S-transferase (GST) in the brain. Supporting data will be collected concerning one GST isoenzyme, Yp, as a myelin- (and oligodendrocyte-) associated enzyme in the mouse brain, and hypothetical roles of the GST's in detoxication and hormone action will be tested by examining the effects of glutathione depletion on the neurotoxicity of triethyltin and on glucocorticoid induction of glycerol-phosphate dehydrogenase in the brain. In a third series of experiments, studies will be initiated concerning expression of ca and GST's during remyelination after cuprizone intoxication and during reactive gliosis resulting from trimethyltin intoxication. Demyelination and gliosis often are consequences of neurotoxicity and the inflammatory response (e.g., in multiple sclerosis). Since ca and GST are multifunctional, it is expected that these enzymes will have important roles in the CNS, perturbation of which could trigger demyelination and/or gliosis and interfere with myelination or remyelination. In addition, the capabilities for remyelination in the CNS and susceptibility to gliosis will depend upon whether the genes for the glial-cell enzymes can be transcribed and translated after the early stages of development.